This grant application addresses one of the top priority areas identified by the National institute for Drug Abuse (NIDA) for "Grand Opportunities" RC2 grants: EPIGENETICS;and specific area identified as: Technologies enabling in vivo imaging of epigenetic markers, modifying enzymes, or effector molecules in the brain. With the recent advances in epigenetic research and improvement in our understanding of various epigenetic mechanisms involved in the development of drug addiction behavior, histone deacetylase (HDAC) Class IIa enzymes HDAC4 and HDAC5 have emerged as important targets for the development of novel therapies for drug addiction. However, for studies on the involvement of different HDACs in the mechanisms of addicted behavior development, the utilization of invasive biopsies of brain tissue is prohibitive in humans due to obvious reasons of traumatism and morbidity. Therefore, in this grant application we propose series of comprehensive in vivo imaging studies in rodents and non-human primates to further assess the efficacy of HDAC Class-IIa specific radiotracers 18F-DFAHA and 18F-TFAHA for non-invasive PET imaging of HDAC4 and HDAC5 activity in the brain in comparison with previously developed, but less specific radiotracer 18F- FAHA. Also, we propose to synthesize potentially even more specific and potent 18F-labeled substrate- radiotracers for PET imaging of HDAC4 and HDAC5 activity in the brain. These novel HDAC Class-IIa specific PET radiotracers can be widely distributed to academic institutions for pre-clinical and clinical research, and which can be integrated with other NIH and privately funded research projects and initiatives within the reasonable timeframe (after completion of this project). The availability of HDAC class and isotype-specific PET radiotracers will facilitate the development of novel HDAC inhibitors by providing the tools for non- invasive, repetitive, and quantitative imaging of expression-activity of different HDAC enzymes in various structures (nuclei) of the brain both in experimental animal models and in human patients. Novel molecular imaging methods and targeted therapies of addiction should generate a significant healthcare-economic and socio-economic impact. PUBLIC HEALTH RELEVANCE: In this grant application we propose series of comprehensive imaging studies in rodents and non-human primates to assess the efficacy of novel radiolabeled agents non-invasive PET imaging of Class-IIa histone deacetylase enzymes in the brain, which have been implicated in the mechanism of development of drug addiction. The availability of HDAC class and isotype-specific PET radiotracers will facilitate the development of novel HDAC inhibitors by providing the tools for non-invasive, repetitive, and quantitative imaging of expression-activity of different HDAC enzymes in various structures (nuclei) of the brain both in experimental animal models and in human patients. Novel molecular imaging methods and targeted therapies of addiction should generate a significant healthcare-economic and socio-economic impact.